Inhibition of metastasis by hexim1 through effects on cell invasion and angiogenesis

ABSTRACT We report on the role of hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers

when compared with matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared with primary mammary tumors in a mouse model of

metastatic breast cancer, the polyoma middle T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of

HEXIM1 expression, hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF-1α protein

allows not only for inhibition of vascular endothelial growth factor-regulated angiogenesis, but also for inhibition of compensatory pro-angiogenic pathways and recruitment of bone

marrow-derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion that can be partly attributed to decreased membrane localization of the 67 kDa laminin

receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus, HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more

than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer. Access

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_Oncogene_ 2005; 24: 5576–5588. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by National Institute of Health grants CA92440 grant to MMM and

R01CA118399 to AAE. WK was supported by a Scholarship for the Development of New Faculty Staff from the Chulalongkorn University in Thailand. The HPLC-MS-MS instrument used for HMBA analysis

was funded by National Science Foundation MRI grant (CHE-0923308) to YX. KS is supported by a US Department of Education GAANN grant (P200A070595-08) to YX. AUTHOR INFORMATION Author notes

* B M Wittmann Present address: 7Current address: Metabolon Inc., Durham, NC 27713, USA, AUTHORS AND AFFILIATIONS * Department of Pharmacology, Case Western Reserve University Cleveland,

Cleveland, OH, USA W Ketchart, B M Wittmann, Y Hu, Y Q Doughman & M M Montano * Department of Chemistry, Cleveland State University, Cleveland, OH, USA K M Smith & Y Xu * Department

of Radiology, Case Western Reserve University Cleveland, Cleveland, OH, USA T Krupka & A A Exner * Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH,

USA P A Rayman & J H Finke * Department of Epidemiology and Biostatistics, Case Western Reserve University Cleveland, Cleveland, OH, USA J M Albert * Center for RNA Molecular Biology,

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Google Scholar CORRESPONDING AUTHOR Correspondence to M M Montano. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary

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on cell invasion and angiogenesis. _Oncogene_ 32, 3829–3839 (2013). https://doi.org/10.1038/onc.2012.405 Download citation * Received: 17 January 2012 * Revised: 21 May 2012 * Accepted: 20

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initiative KEYWORDS * HEXIM1 * breast cancer * metastasis * angiogenesis